Biological Functions of the KDM2 Family of Histone Demethylases.

The histone lysine demethylase 2 (KDM2) family of α-Ketoglutarate-Fe++-dependent dioxygenases were the first Jumonji-domain-containing proteins reported to harbor demethylase activity. This landmark discovery paved the way for the characterization of more than 25 enzymes capable of demethylating lysine residues on histones-an epigenetic modification previously thought to be irreversible. The KDM2 family is comprised of KDM2A and KDM2B which share significant structural similarities and demethylate lysine 36 on histone H3. However, they exert distinct cellular functions and are frequently deregulated in a broad spectrum of human cancers. With the advent of next generation sequencing and development of genetically engineered mouse models, it was shown that KDM2A and KDM2B play critical roles in stem cell biology, somatic cell reprograming, and organismal development by regulating cell fate and lineage commitment decisions. Thus, understanding the biochemistry and elucidating the context-dependent function of these enzymes is an emerging new frontier for the development of small molecule inhibitors to treat cancer and other diseases.

Loss of the transforming growth factor-ß effector ß2-Spectrin promotes genomic instability.

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ß/mothers against decapentaplegic homolog 3 adaptor ß2-Spectrin (ß2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ß2SP supports DNA repair through ß2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ß2SP leads to decreased Fancd2 levels and sensitizes ß2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ß stimulation is regulated by the ß2SP/mothers against decapentaplegic homolog 3 complex. CONCLUSION: Dysfunctional transforming growth factor ß/ß2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

The Lkb1 metabolic sensor maintains haematopoietic stem cell survival.

Haematopoietic stem cells (HSCs) can convert between growth states that have marked differences in bioenergetic needs. Although often quiescent in adults, these cells become proliferative upon physiological demand. Balancing HSC energetics in response to nutrient availability and growth state is poorly understood, yet essential for the dynamism of the haematopoietic system. Here we show that the Lkb1 tumour suppressor is critical for the maintenance of energy homeostasis in haematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all haematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The haematopoietic effects are largely independent of Lkb1 regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling. Instead, these data define a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in haematopoietic cells through a novel metabolic checkpoint.

Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis.

INTRODUCTION: Basal-like breast cancer (BLBC) is an aggressive subtype often characterized by distant metastasis, poor patient prognosis, and limited treatment options. Therefore, the discovery of alternative targets to restrain its metastatic potential is urgently needed. In this study, we aimed to identify novel genes that drive metastasis of BLBC and to elucidate the underlying mechanisms of action. METHODS: An unbiased approach using gene expression profiling of a BLBC progression model and in silico leveraging of pre-existing tumor transcriptomes were used to uncover metastasis-promoting genes. Lentiviral-mediated knockdown of interleukin-13 receptor alpha 2 (IL13Ralpha2) coupled with whole-body in vivo bioluminescence imaging was performed to assess its role in regulating breast cancer tumor growth and lung metastasis. Gene expression microarray analysis was followed by in vitro validation and cell migration assays to elucidate the downstream molecular pathways involved in this process. RESULTS: We found that overexpression of the decoy receptor IL13Ralpha2 is significantly enriched in basal compared with luminal primary breast tumors as well as in a subset of metastatic basal-B breast cancer cells. Importantly, breast cancer patients with high-grade tumors and increased IL13Ralpha2 levels had significantly worse prognosis for metastasis-free survival compared with patients with low expression. Depletion of IL13Ralpha2 in metastatic breast cancer cells modestly delayed primary tumor growth but dramatically suppressed lung metastasis in vivo. Furthermore, IL13Ralpha2 silencing was associated with enhanced IL-13-mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and impaired migratory ability of metastatic breast cancer cells. Interestingly, genome-wide transcriptional analysis revealed that IL13Ralpha2 knockdown and IL-13 treatment cooperatively upregulated the metastasis suppressor tumor protein 63 (TP63) in a STAT6-dependent manner. These observations are consistent with increased metastasis-free survival of breast cancer patients with high levels of TP63 and STAT6 expression and suggest that the STAT6-TP63 pathway could be involved in impairing metastatic dissemination of breast cancer cells to the lungs. CONCLUSION: Our findings indicate that IL13Ralpha2 could be used as a promising biomarker to predict patient outcome and provide a rationale for assessing the efficacy of anti-IL13Ralpha2 therapies in a subset of highly aggressive basal-like breast tumors as a strategy to prevent metastatic disease.

Hippo signaling regulates differentiation and maintenance in the exocrine pancreas.

BACKGROUND & AIMS: The Hippo signaling pathway is a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to humans. In this study, we investigated the role of the core Hippo kinases-Mst1 and Mst2-in pancreatic development and homeostasis. METHODS: We used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2 (Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice), the mammalian orthologs of Drosophila Hippo. We used a transgenic approach to overexpress Yap, the downstream mediator of Hippo signaling, in the developing pancreas of mice. RESULTS: Contrary to expectations, the pancreatic mass of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice was reduced compared with wild-type mice, largely because of postnatal de-differentiation of acinar cells into duct-like cells. Development of this phenotype coincided with postnatal reactivation of YAP expression. Ectopic expression of YAP during the secondary transition (a stage at which YAP is normally absent) blocked differentiation of the endocrine and exocrine compartments, whereas loss of a single Yap allele reduced acinar de-differentiation. The phenotype of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice recapitulated cellular and molecular changes observed during chemical-induced pancreatitis in mice. CONCLUSIONS: The mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice.

Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells.

Sustained expression of the histone demethylase, KDM2B (Ndy1/FBXL10/JHDM1B), bypasses cellular senescence in primary mouse embryonic fibroblasts (MEFs). Here, we show that KDM2B is a conserved regulator of lifespan in multiple primary cell types and defines a program in which this chromatin-modifying enzyme counteracts the senescence-associated down-regulation of the EZH2 histone methyltransferase. Senescence in MEFs epigenetically silences KDM2B and induces the tumor suppressor miRNAs let-7b and miR-101, which target EZH2. Forced expression of KDM2B promotes immortalization by silencing these miRNAs through locus-specific histone H3 K36me2 demethylation, leading to EZH2 up-regulation. Overexpression of let-7b down-regulates EZH2, induces premature senescence, and counteracts immortalization of MEFs driven by KDM2B. The KDM2B-let-7-EZH2 pathway also contributes to the proliferation of immortal Ink4a/Arf null fibroblasts suggesting that, beyond its anti-senescence role in primary cells, this histone-modifying enzyme functions more broadly in the regulation of cellular proliferation.

Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus.

The histone H3 demethylase Not dead yet-1 (Ndy1/KDM2B) is a physiological inhibitor of senescence. Here, we show that Ndy1 is down-regulated during senescence in mouse embryonic fibroblasts (MEFs) and that it represses the Ink4a/Arf locus. Ndy1 counteracts the senescence-associated down-regulation of Ezh2, a component of polycomb-repressive complex (PRC) 2, via a JmjC domain-dependent process leading to the global and Ink4a/Arf locus-specific up-regulation of histone H3K27 trimethylation. The latter promotes the Ink4a/Arf locus-specific binding of Bmi1, a component of PRC1. Ndy1, which interacts with Ezh2, also binds the Ink4a/Arf locus and demethylates the locus-associated histone H3K36me2 and histone H3K4me3. The combination of histone modifications driven by Ndy1 interferes with the binding of RNA Polymerase II, resulting in the transcriptional silencing of the Ink4a/Arf locus and contributing to the Ndy1 immortalization phenotype. Other studies show that, in addition to inhibiting replicative senescence, Ndy1 inhibits Ras oncogene-induced senescence via a similar molecular mechanism.

Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process.

A common integration site, cloned from MoMuLV-induced rat T cell lymphomas, was mapped immediately upstream of Not dead yet-1 (Ndy1)/KDM2B, a gene expressed primarily in testis, spleen, and thymus, that is also known as FBXL10 or JHDM1B. Ndy1 encodes a nuclear, chromatin-associated protein that harbors Jumonji C (JmjC), CXXC, PHD, proline-rich, F-box, and leucine-rich repeat domains. Ndy1 and its homolog Ndy2/KDM2A (FBXL11 or JHDM1A), which is also a target of provirus integration in retrovirus-induced lymphomas, encode proteins that were recently shown to possess Jumonji C-dependent histone H3 K36 dimethyl-demethylase or histone H3 K4 trimethyl-demethylase activities. Here, we show that mouse embryo fibroblasts engineered to express Ndy1 or Ndy2 undergo immortalization in the absence of replicative senescence via a JmjC domain-dependent process that targets the Rb and p53 pathways. Knockdown of endogenous Ndy1 or expression of JmjC domain mutants of Ndy1 promote senescence, suggesting that Ndy1 is a physiological inhibitor of senescence in dividing cells and that inhibition of senescence depends on histone H3 demethylation.

Differentiation of fetal hematopoietic stem cells requires ARID4B to restrict autocrine KITLG/KIT-Src signaling.

Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of the hematopoietic stem/progenitor cell (HSPC) compartment. To retain the HSC self-renewal activity, KIT, a receptor tyrosine kinase, in HSCs is activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing HSC differentiation. Conditional Arid4b knockout in mouse hematopoietic cells blocks fetal HSC differentiation, preventing hematopoiesis. Mechanistically, ARID4B-deficient HSCs self-express KITLG and overexpress KIT. As to downstream pathways of KITLG/KIT signaling, inhibition of Src family kinases rescues the HSC differentiation defect elicited by ARID4B loss. In summary, the intrinsic ARID4B-KITLG/KIT-Src axis is an HSPC regulatory program that enables the differentiation state, while KIT stimulation by KITLG from niche cells preserves the HSPC undifferentiated pool.

Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of insulin receptor substrate-1 (IRS-1) and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR.

In normal physiological states mTOR phosphorylates and activates Akt. However, under diabetic-mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639. The molecular basis for the differential effect of mTOR signaling on Akt is poorly understood. Here, it has been shown that knockdown of mTOR, Raptor, and mLST8, but not Rictor and mSin1, suppresses insulin-stimulated phosphorylation of IRS-1 at Ser-636/639 and stabilizes IRS-1 after long term insulin stimulation. This phosphorylation depends on the PI 3-kinase/PDK1 axis but is Akt-independent. At the molecular level, Raptor binds the SAIN (Shc and IRS-1 NPXY binding) domain of IRS-1 and regulates the phosphorylation of IRS-1 at Ser-636/639 by mTOR. IRS-1 lacking the SAIN domain does not interact with Raptor, is not phosphorylated at Ser-636/639, and favorably interacts with PI 3-kinase. Overall, these data provide new insights in the molecular mechanisms by which mTORC1 inhibits PI 3-kinase/Akt signaling at the level of IRS-1 and suggest that mTOR signaling toward Akt is scaffold-dependent.

BAP1 is a haploinsufficient tumor suppressor linking chronic pancreatitis to pancreatic cancer in mice.

Chronic pancreatitis represents a risk factor for the development of pancreatic cancer. We find that heterozygous loss of histone H2A lysine 119 deubiquitinase BAP1 (BRCA1 Associated Protein-1) associates with a history of chronic pancreatitis and occurs in 25% of pancreatic ductal adenocarcinomas and 40% of acinar cell carcinomas. Deletion or heterozygous loss of Bap1 in murine pancreata causes genomic instability, tissue damage, and pancreatitis with full penetrance. Concomitant expression of KrasG12D leads to predominantly intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, while pancreatic intraepithelial neoplasias are rarely detected. These lesions progress to metastatic pancreatic cancer with high frequency. Lesions with histological features mimicking Acinar Cell Carcinomas are also observed in some tumors. Heterozygous mice also develop pancreatic cancer suggesting a haploinsufficient tumor suppressor role for BAP1. Mechanistically, BAP1 regulates genomic stability, in a catalytic independent manner, and its loss confers sensitivity to irradiation and platinum-based chemotherapy in pancreatic cancer.

Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation.

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer.

Platinum drugs are used in first-line to treat ovarian cancer, but most of the patients eventually generate resistance after treatment with these drugs. Although both c-Myc and EZH2 have been implicated in regulating cisplatin resistance in ovarian cancer, the interplay between these two regulators is poorly understood. Using RNA sequence analysis (RNA-seq), for the first time we find that miR-137 level is extremely low in cisplatin resistant ovarian cancer cells, correlating with higher levels of c-Myc and EZH2 expression. Further analyses indicate that in resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin. Inhibition of c-Myc-miR-137-EZH2 pathway re-sensitizes resistant cells to cisplatin. Both in vivo and in vitro analyses indicate that cisplatin treatment activates c-Myc-miR-137-EZH2 pathway. Importantly, elevated c-Myc-miR-137-EZH2 pathway in resistant cells is sustained by dual oxidase maturation factor 1 (DUOXA1)-mediated production of reactive oxygen species (ROS). Significantly, clinical studies further confirm the activated c-Myc-miR-137-EZH2 pathway in platinum drug-resistant or recurrent ovarian cancer patients. Thus, our studies elucidate a novel role of miR-137 in regulating c-Myc-EZH2 axis that is crucial to the regulation of cisplatin resistance in ovarian cancer.

Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer.

Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression in normal lungs to identify candidates associated with lung cancer. Indeed, most of the lung-enriched genes identified in our analysis have known or suspected roles in lung cancer. We focused on the gene encoding neuron-derived neurotrophic factor (NDNF), which had not yet been associated with lung cancer. We determined that NDNF was preferentially expressed in the normal adult lung and that its expression was decreased in human lung adenocarcinoma and a mouse model of this cancer. Higher expression of NDNF was associated with better clinical outcome of patients with lung adenocarcinoma. Purified NDNF inhibited proliferation of lung cancer cells, whereas silencing NDNF promoted tumor cell growth in culture and in xenograft models. We determined that NDNF is downregulated through DNA hypermethylation near CpG island shores in human lung adenocarcinoma. Furthermore, the lung cancer-related DNA hypermethylation sites corresponded to the methylation sites that occurred in tissues with low NDNF expression. Thus, by analyzing the tissue-specific secretome, we identified a tumor-suppressive factor, NDNF, which is associated with patient outcomes in lung adenocarcinoma.

Predicting CTCF-mediated chromatin interactions by integrating genomic and epigenomic features.

The CCCTC-binding zinc-finger protein (CTCF)-mediated network of long-range chromatin interactions is important for genome organization and function. Although this network has been considered largely invariant, we find that it exhibits extensive cell-type-specific interactions that contribute to cell identity. Here, we present Lollipop, a machine-learning framework, which predicts CTCF-mediated long-range interactions using genomic and epigenomic features. Using ChIA-PET data as benchmark, we demonstrate that Lollipop accurately predicts CTCF-mediated chromatin interactions both within and across cell types, and outperforms other methods based only on CTCF motif orientation. Predictions are confirmed computationally and experimentally by Chromatin Conformation Capture (3C). Moreover, our approach identifies other determinants of CTCF-mediated chromatin wiring, such as gene expression within the loops. Our study contributes to a better understanding about the underlying principles of CTCF-mediated chromatin interactions and their impact on gene expression.

Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors.

KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.

DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer.

The acquisition of resistance is a major obstacle to the clinical use of platinum drugs for ovarian cancer treatment. Increase of DNA damage response is one of major mechanisms contributing to platinum-resistance. However, how DNA damage response is regulated in platinum-resistant ovarian cancer cells remains unclear. Using quantitative high throughput combinational screen (qHTCS) and RNA-sequencing (RNA-seq), we show that dual oxidase maturation factor 1 (DUOXA1) is overexpressed in platinum-resistant ovarian cancer cells, resulting in over production of reactive oxygen species (ROS). Elevated ROS level sustains the activation of ATR-Chk1 pathway, leading to resistance to cisplatin in ovarian cancer cells. Moreover, using qHTCS we identified two Chk1 inhibitors (PF-477736 and AZD7762) that re-sensitize resistant cells to cisplatin. Blocking this novel pathway by inhibiting ROS, DUOXA1, ATR or Chk1 effectively overcomes cisplatin resistance in vitro and in vivo. Significantly, the clinical studies also confirm the activation of ATR and DOUXA1 in ovarian cancer patients, and elevated DOUXA1 or ATR-Chk1 pathway correlates with poor prognosis. Taken together, our findings not only reveal a novel mechanism regulating cisplatin resistance, but also provide multiple combinational strategies to overcome platinum-resistance in ovarian cancer.

Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance.

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2-STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11-JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS-IL-11-JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.

Lysine-specific histone demethylases in normal and malignant hematopoiesis.

The epigenetic control of gene expression is central to the development of the hematopoietic system and the execution of lineage-specific transcriptional programs. During the last 10 years, mounting evidence has implicated the family of lysine-specific histone demethylases as critical regulators of normal hematopoiesis, whereas their deregulation is found in a broad spectrum of hematopoietic malignancies. Here, we review recent findings on the role of these enzymes in normal and malignant hematopoiesis and highlight how aberrant epigenetic regulation facilitates hematopoietic cell transformation through subversion of cell fate and lineage commitment programs.

Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis.

The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context.